16, 17 - Cancer Flashcards
Majority of antitumour antibiotics are isolated and discovered from ______
Microbial fermentations
What are bleomycins? What is the MOA?
- Cytotoxic glycopeptide antibiotics
- Believed that bleomycin chelates metal ions (mostly Fe2+ and Cu2+), producing a pseudoenzyme that reacts w/ oxygen to produce free radicals that cause DNA strand breaks, ultimately leading to cytotoxic event
What determines therapeutic efficacy of bleomycins?
- Dose-dependent pneumonitis (lung toxicity)
- May be related to absence of bleomycin hydrolase in the lungs of some px
Describe the bleomycin DNA strand break model
- dsDNA cleavage by a single bleomycin molecule requires bleomycin reactivation and reorganization during or after cleavage of first strand of DNA
- Key to reorganization is the linker and flexibility of the bithiazole tail that is bound by partial intercalation
What form of bleomycin is responsible for initiating DNA damage? How is this formed?
- Bleomycin binding to Fe2+, followed by oxygen binding and reduction by a reductant
- This intermediate is responsible
What is required for activated bleomycin to be generated?
- Bleomycin-Cu(2) must be reduced to bleomycin-Cu(1) intracellularly
- Cu(1) must dissociate from bleomycin and Fe(2) must bind
- Once Fe(2) is bound, the chemistry to form activated bleomycin ensues
Describe the structure of anthracyclins
Planar oxidized anthracene ring fused to a cyclohexane ring that is attached via glycosidic linkage to amino sugar
What is the general mechanism of anthracyclins?
Intercalation followed by inhibition of topoisomerase 2 leading to DNA strand breakage and apoptosis
Which are the 5 accepted anthracyclins?
- Doxorubicin
- Daunorubicin
- Epirubicin
- Valrubicin
- Idarubicin
What is the MOA of doxorubicin?
- Stabilizes topoisomerase 2 complex after it has broken the DNA chain for replication, preventing DNA double helix from being resealed
- Generation of free radicals and resulting oxidative stress causing cell death and membrane damage and DNA strand breaks
How does doxorubicin enter a cell?
- Diffusion
- Via the SLC transporter
Why is the use of doxorubicin limited? What causes this?
- Cardiotoxicity that leads to congestive heart failure (above 350 mg/m^2)
- Caused by redox cycling (doxorubicin is a quinone that is reduced to a semiquinone free radical, which reacts w/ oxygen to reform quinone)
- Also doxorubicin forms a strong complex w/ Fe3+, which can be reduced to Fe2+ complex, which then forms a hydroxyl radical that is extremely reactive and damaging to cell membranes and proteins
What is dexrazoxane? What is the MOA?
- Cardioprotective agent against doxorubicin-induced cardiotoxicity in tx of metastatic breast cancer
- Crosses cell membranes and hydrolyzed to ADR-925 inside the cell
What are some anticancer drugs that target topoisomerase 2?
- Etoposide
- Doxorubicin
- Mitoxantrone
- Amsacrine
What is the function of DNA topoisomerase 2 in the cell? What does it require to function?
- DNA replication
- DNA recombination
- Chromosome condensation/ decondensation
- Segregation of sister chromatids
- Requires an ATP cofactor to drive the reaction
What do topoisomerase 2 poisons do?
- Cause single and double strand DNA breaks
- Increase topoisomerase 2 levels and renders cells hypersensitive
- Stabilize topoisomerase 2-DNA covalent complexes
When is topoisomerase 2 most highly expressed?
When cells are dividing
What do topoisomerase 2 catalytic inhibitors do?
- Don’t cause DNA strand breaks
- Don’t stabilize topoisomerase 2-DNA cleavable complexes
What is the MOA of etoposide and teniposide?
- Topoisomerase 2 inhibitors
- Act in late G2/M phase of cell cycle by preventing cells from entering mitosis
What limits the use of etoposide?
- It causes severe myelosuppression
- May lead to a secondary leukemia several years later (derived from etoposide DNA damage)
What causes etoposide drug resistance?
MDR (multidrug resistance) protein being over expressed
What is podophyllotoxin?
- Antimitotic
- Acts by binding to tubulin
What do amsacrine and mitoxantrone work?
Inhibit human topoisomerase 2 by inserting into enzyme-mediated DNA cleavage sites
Which drugs are camptothecins? How do they work?
- Topotecan and irinotecan
- Topoisomerase 1 inhibitors
- Both have addition of basic amine side chains to increase water solubility
What is the function of topoisomerase enzymes?
- Control supercoiling of DNA, maintaining proper topological state or superhelical tension
- Topoisomerase 1 causes single strand breaks; topoisomerase 2 causes double strand breaks
What is the MOA of camptothecins?
- Bind to DNA-topoisomerase 1 complex after strand cleavage, w/ planar ring structure intercalating w/ DNA, stabilizing cleavable complex, preventing realignment and resealing
- During DNA replication, stabilized complex leads to double-stranded DNA breaks and cell death
What is the effect of dactinomycin?
- Binds non-covalently to double-stranded DNA by intercalation of planar phenoxazone ring between adjacent guanine-cytosine bases, inhibiting DNA function
- Peptide loops sit in minor groove, providing additional intercalation
What are the indications for topotecan and irinotecan?
- Topotecan = metastatic carcinoma of ovaries after failure of initial or subsequent therapy; second line for small cell lung cancer
- Irinotecan = first line for px w/ metastatic carcinoma of colon or rectum
What does mitomycin C do?
- Bio-reductive alkylating agent that can react w/ DNA nucleophiles, following bioactivation (methanol eliminating, aziridine ring opening) to give an electrophilic intermediate
- Alkylation preferred at GC rich regions of DNA, w/ guanine alkylation at 2-amino group
What does alkaloids mean?
Natural products containing mostly basic nitrogen atoms, usually has a nitrogen containing ring system as key functional group
Describe the structure of Vinca alkaloids
Two conjoined groups – catharanthine moiety (indole, azonine, piperidine ring systems) and vindoline moiety (dihydroindole, cyclohexane, pyrrolidine, piperidine)
Which drugs are vinca alkaloids?
- Vinblastine
- Vincristine
- Vinorelbine
What is the effect of vinca alkaloids?
Accumulate in cells, bind to tubulin and disrupt formation of mitotic spindle, inhibiting microtubule assembly
What is the function of the mitotic spindle?
- Function as cell’s cytoskeleton and maintain cellular shape
- Involved in movement of chromosome during mitosis and cell signaling
What is a concern w/ vinca alkaloids? What is used to fix this?
- Extravasation (leakage of infused substances resulting in tissue destruction)
- Hyaluronidase promotes re-absorption of tissue fluids
What is the effect of taxanes?
Bind to tubulin (at a different site than Vinca’s), stabilizing the microtubule and preventing depolymerization, blocking mitosis
Which drugs are taxanes?
Taxol and taxotere
What is the major difference between vinca alkaloids and taxanes?
- Vinca’s (vinblastine) binds on the plus end of of tubulin
- Taxanes (paclitaxel) binds on interior surface
What are advantages to epothilones over taxanes?
For epothilones, conversion of lactone to lactam offers greater metabolic stability and water solubility
When are protein kinase inhibitors used?
In combination w/ more traditional chemotherapeutics to achieve better outcomes
What are protein kinases important for?
Signal transduction, differentiation, growth, regulation and division of cells
What is the effect of tyrosine kinase inhibitors?
Limit catalytic activity of EGFR
Kinase inhibitors mimic ____
ATP
___ was the first approved kinase inhibitor
Imatinib
What does imatinib bind to?
ATP binding site of the c-Abl tyrosine kinase domain
What is the difference between type 1 and type 2 binding of kinase inhibitors?
- Type 1 inhibitors bind to active conformation of the kinase, w/ aspartate residue of DFG motif pointing into ATP-binding pocket
- Type 2 inhibitors bind and stabilize inactive conformation of kinase w/ the flipped aspartate residue facing outward of binding pocket
What is the difference between the kinase inhibitor binding models?
- Type 1 inhibitors have 2 hydrophobic pockets and H-bond to hinge unit in adenine site
- Type 2 inhibitors have 1 hydrophobic pocket, 1 allosteric pocket, and 2 sites for H-bonds (hinge and allosteric)
What is a limitation to tyrosine kinase inhibitors?
Long term use results in cardiotoxicity for some
What are the mechanisms of cardiotoxicity for tyrosine kinase inhibitors?
1) On-target toxicity due to inhibiting intended target
2) Off-target toxicity due to a kinase not intended to be inhibited
3) ATP-binding proteins and other proteins can bind inhibitors
What is lapatinib?
- Small molecule tyrosine kinase inhibitor used to treat breast cancers that overexpress HER2
- Strongly inhibits tyrosine kinase activity of HER2 and EGFR by directly competing w/ ATP
What is trastuzumab?
- Humanized antibody used to treat early stage breast cancers that overexpress HER2
- Binds to extracellular domain of HER2 receptor
- MOA not well understood; may promote internalization and degradation of the receptor; may also induce immune response to attack the cell, so can be cardiotoxic
What is the function of bevacizumab? What is its indication?
- Neutralizes biologic activity of human vascular endothelial growth factor (VEGF)
- Used to treat metastatic colorectal cancer and others
What is the function of cetuximab? What is its indication?
- Binds to human epidermal growth factor receptor (EGFR)
- Used to treat metastatic colorectal carcinoma
What is the function of ipilimumab? What is its indication?
- Binds to and blocks human cytotoxic T lymphocyte-associated antigen 4
- Tx of unresectable or metastatic melanoma
What is the function of nivolumab? What is its indication?
- Inhibits T-cell proliferation by binding to programmed cell death protein 1
- Tx metastatic BRAF V600 wild-type melanoma
What is the function of ofatumumab? What is its indication?
- Binds to CD20 molecule leading to cell death
- Tx of px w/ chronic lymphocytic leukemia (CLL)
What is the function of panitumumab? What is its indication?
- Binds to human EGFR
- Tx for metastatic colorectal carcinoma
What is the function of rituximab? What is its indication?
- Binds to CD20
- Used to tx non-Hodgkin’s lymphoma and B-cell chronic lymphocytic leukemia
What is the effect of bortezomib?
- Inhibits proteasome by forming covalent boron-threonine bond at active site
- Leads to cell cycle arrest and induction of apoptosis
What is the function of proteasomes?
Degrade unneeded or damaged proteins by proteolysis of peptide bonds
Which drugs target the protease activity of the proteasome?
Bortezomib and carfilzomib
